Bystander effects induced by the interaction between urothelial cancer cells and irradiated adipose tissue-derived stromal cells in urothelial carcinoma

Cell–cell interactions between cancer cells and neighboring adipose tissue-derived stromal cells (ATSCs) are known to regulate the aggressiveness of cancer cells. In addition, the radiation-induced bystander effect is an important modulator of cancer cell kinetics. Radiation therapy is often given for urinary cancer, but the biological effects of the irradiated cancer stroma, including adipose tissue, on urothelial carcinoma (UC) remain unclear. We investigated the bystander effect of irradiated ATSCs on UC using a collagen gel culture method to replicate irradiated ATSC–cancer cell interactions after a single 12-Gy dose of irradiation. Proliferative activity, invasive capacity, protein expression and nuclear translocation of p53 binding protein-1 (53BP1) were analyzed. Irradiated ATSCs significantly inhibited the growth and promoted the apoptosis of UC cells in comparison to non-irradiated controls. The invasiveness of UC cells was increased by irradiated ATSCs, but not irradiated fibroblasts. Nuclear translocation of 53BP1 protein due to the bystander effect was confirmed in the irradiated group. Irradiated ATSCs regulated the expressions of the insulin receptor, insulin-like growth factor-1 and extracellular signal-regulated kinase-1/2 in UC. In conclusion, the bystander effect of irradiated ATSCs is a critical regulator of UC, and the actions differed depending on the type of mesenchymal cell involved. Our alternative culture model is a promising tool for further investigations into radiation therapy for many types of cancer.